1. Field of the Invention
The present invention relates generally to the fields of developmental biology and molecular biology. More particularly, it concerns a striated muscle RING finger protein (MURF) involved in microtubule and intermediate filament stabilization of striated muscle cells.
2. Description of Related Art
The RING-finger is an unusual type of Cys-His zinc-binding motif found in a growing number of proteins with roles in signal transduction, gene transcription, differentiation, and morphogenesis (Borden, 1998; Saurin et al., 1996). A RING-B-box-coiled-coil (RBCC) subclass of RING-finger proteins contains an N-terminal RING-finger followed by a single or multiple additional zinc-finger domains, termed B-boxes, and a leucine-rich coiled-coil domain (Borden, 1998). The tripartite organization of these domains is evolutionarily conserved, suggesting an integrated and functional role for this overall protein structure. It should also be noted that the RING-finger and B-box motifs have been identified based on sequence homologies and are predicted to function as zinc-binding domains. However, their precise functions have not been fully elucidated. There is evidence suggesting that the RING-finger, B-box and coiled-coil domains mediate protein-protein interactions.
Several RBCC proteins have been implicated in oncogenesis. The RBCC member PML becomes fused to the retinoic acid receptor alpha in acute promyelocytic leukemia (De The et al., 1991). Similarly, the RBCC proteins BRCA1, Cb1, Rfp, TIF1, and MDM2 have been demonstrated to be oncogenic when fused to other factors through chromosomal translocation events (Saurin et al., 1996). Other RBCC proteins have been implicated in signal transduction, organellar biogenesis, chromosomal dynamics, viral pathogenesis, transcription, and developmental patterning (Saurin et al., 1996).
Recently, a complex congenital human disease, Opitz G/BBB syndrome, was shown to result from mutations in the RBCC protein, Mid1 (Quaderi et al., 1997). Opitz G/BBB syndrome is characterized by abnormalities of midline structures, including hypertelorism, clefts of lip and palate, larygotracheoesophageal defects, hypospadias, imperforate anus, and developmental delay. The Mid1 gene product is widely expressed during development and interacts with microtubules throughout the cell cycle (Cainarca et al., 1999). Overexpression of Mid1 leads to a stable population of microtubules resistant to depolymerization (Schweiger et al., 1999). Interestingly, mutations of Mid1 that are linked to Opitz G/BBB syndrome severely diminish the ability of Mid1 to interact with microtubules, suggesting that Mid1-microtubule interaction and/or microtubule dynamics are involved in the processes required for normal development of the midline structures affected in Opitz G/BBB syndrome.
Many questions remain regarding the function of Mid1-type proteins and their interactions with microtbules. Nonetheless, it is clear that such molecules play an important role in development, function and pathology of a wide variety of cell types.